ABSTRACT African trypanosomiasis is a deadly disease caused by Trypanosoma parasites that are transmitted by Tsetse flies. Human African trypanosomiasis (HAT) is characterized by trypanosomes that replicate in the blood system (stage 1 infection) and those that cross the blood brain barrier to infect the central nervous system (stage 2 infection). The disease causes personality changes and psychosis, which progresses through periods of somnolescence before coma and death. The current drugs are toxic and often require multiple injections thus complicating case-management in resource-poor settings. Naegleria fowleri is a pathogen that causes primary amebic meningitis (PAM). N. fowleri in contaminated freshwater enter the nasal cavity and then the brain to cause hemorrhage and necrosis. Death occurs within a week of infection and >95% of cases are fatal. Children under 13 are particularly at risk. The optimum treatment for PAM has not been defined. Both amphotericin B, which is not FDA-approved for this indication, and miltefosine have been used with mixed results. New drugs for both parasite infections are needed Microtubules (MTs), comprising alpha- and beta-tubulins, are essential to cell homeostasis and inhibition of tubulin polymerization has been tested as a means to develop novel anti-parasitics. In contrast, tubulin polymerization promoters (i.e. MT-stabilizing agents) have not been investigated. The preliminary data presented show that MT-stabilizers that are being developed as experimental therapeutics for neurodegenerative diseases kill both Trypanosoma brucei and N. fowleri in culture with potencies the equivalent or better than the current anti-parasitic drugs. One lead compound, 51459, has undergone extensive pharmacokinetic (PK) profiling in mice. These studies suggest that a single 10 mg/kg oral dose of 51459 leads to sustained micromolar compound concentrations in the brain that are greater than or equal to the doses needed to kill the parasites. The combination, therefore, of 51459's potency and straightforward dosing regimen presents an opportunity to investigate its potential as a novel therapeutic of HAT and/or PAM. Accordingly, investigators from the Center for Discovery and Innovation in Parasitic Diseases at the Skaggs School of Pharmacy and Pharmaceutical Sciences, UC San Diego, have the following objectives: (1) synthesize 200 mg of 51549 to enable both tolerability and efficacy studies in mice; (2) conduct tolerability studies upon single and repeated administration of 51549; (3) determine the in vivo efficacy of 51549 in mice infected with T. brucei or N. fowleri; (4) perform X-ray crystallography by co-crystallizing 51549 with the tubulin target from the two parasites of interest. These studies will provide new mechanistic data on how 51549 and related compounds bind to and promote MT- stabilization, which, in turn, will aid the design of new and potentially improved MT-stabilizing compounds for the treatment of parasitic infections.